The treatment of pain conditions is of great importance in medicine. There is currently a world-wide need for additional pain therapy. The pressing requirement for a specific treatment of pain conditions is documented in the large number of scientific works that have appeared recently in the field of applied analgesics.
PAIN is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (IASP, Classification of chronic pain, 2nd Edition, IASP Press (2002), 210). Although it is a complex process influenced by both physiological and psychological factors and is always subjective, its causes or syndromes can be classified. Pain can be classified based on temporal, aetiological or physiological criteria. When pain is classified by time, it can be acute or chronic. Aetiological classifications of pain are malignant or non-malignant. A third classification is physiological, which includes nociceptive pain (results from detection by specialized transducers in tissues attached to A-delta and C-fibres), that can be divided into somatic and visceral types of pain, and neuropathic pain (results from irritation or damage to the nervous system), that can be divided into peripheral and central neuropathic pain. Pain is a normal physiological reaction of the somatosensory system to noxious stimulation which alerts the individual to actual or potential tissue damage. It serves a protective function of informing us of injury or disease, and usually remits when healing is complete or the condition is cured. However, pain may result from a pathological state characterized by one or more of the following: pain in the absence of a noxious stimulus (spontaneous pain), increased duration of response to brief stimulation (ongoing pain or hyperpathia), reduced pain threshold (allodynia), increased responsiveness to suprathreshold stimulation (hyperalgesia), spread of pain and hyperalgesia to uninjured tissue (referred pain and secondary hyperalgesia), and abnormal sensations (e.g., dysesthesia, paresthesia).
Over twenty million patients have surgical procedures each year. Postsurgical pain (interchangeably termed, post-incisional pain), or pain that occurs after surgery or traumatic injury, is a serious and often intractable medical problem. Pain is usually localized within the vicinity of the surgical site. Post-surgical pain can have two clinically important aspects, namely resting pain, or pain that occurs when the patient is not moving and mechanical pain which is exacerbated by movement (coughing/sneezing, getting out of bed, physiotherapy, etc.). The major problem with post-surgical pain management for major surgery is that the drugs currently used have a variety of prominent side effects that delay recovery, prolong hospitalization and subject certain vulnerable patient groups to the risk of serious complications.
The three major classes of pharmaceutical drugs used to treat post-surgical pain are the opioid analgesics, local anesthetics, and the non-steroidal anti-inflammatory drugs (NSAID). Two of these classes of drugs, the opioid analgesics and NSAIDs, are typically administered systemically while the local anesthetics (e.g. channel blockers) are administered non-systemically during surgery.
The systemic administration of drugs to relieve pain after surgery is frequently inadequate. For example, systemic administration of opioids after surgery may cause nausea, the inhibition of bowel function, urinary retention, inhibition of pulmonary function, cardiovascular effects, and sedation.
“Post-surgical pain” (interchangeably termed “post-operative”, “post-incisional” or “posttraumatic pain”) refers to pain arising or resulting from an external trauma or injury such as a cut, puncture, incision, tear, or wound into tissue of an individual (including those that arise from all surgical procedures, whether invasive or non-invasive). As used herein, “post-surgical pain” does not include pain that occurs without an external physical trauma. In some embodiments, post-surgical pain is internal or external pain, and the wound, cut, trauma, tear or incision may occur accidentally (as with a traumatic wound) or deliberately (as with a surgical incision). Infections and/or physical or chemical injuries affecting the wound area can exacerbate and prolong post-surgical pain. As used herein, “pain” includes nociception and the sensation of pain, and pain can be assessed objectively and subjectively, using pain scores and other methods, e.g., with protocols well-known in the art. Post-surgical pain, as used herein, includes resting (also known as spontaneous, persistent or ongoing) pain and evoked pain (pain evoked by stimulation). Evoked pain can be classified as allodynia (i.e., pain due to a stimulus that does not normally provoke pain) and hyperalgesia (i.e., increased response to a stimulus that is normally painful). Stimuli can be thermal or mechanical (tactile) in nature. Mechanical and/or thermal allodynia and/or hyperalgesia can occur in the primary wound area (i.e., primary allodynia or hyperalgesia) or expand to adjacent and surrounding areas that become sensitized (i.e., secondary allodynia or hyperalgesia). Therefore, the pain is characterized by thermal hypersensitivity, mechanical hypersensitivity and/or resting pain (e.g. pain in the absence of external stimuli). Hyperpathia, characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold. Hyperpathia may occur with allodynia, hyperesthesia, hyperalgesia, or dysesthesia, and faulty identification and localization of the stimulus, delay, radiating sensation, and after-sensation may be present, and the pain is often explosive in character. The pain can be primary (e.g., resulting directly from the pain-causing event) or secondary pain (e.g., pain associated with, but not directly resulting, from the pain-causing event). Further, the pain can be acute or chronic. Acute pain results from the external trauma (cut, puncture, incision, tear, or wound), including that arising from all surgical procedures, and can be mild and last seconds, minutes or hours, or it can be severe and last for weeks or months. In most cases, acute pain does not last longer than three months, and it disappears when the underlying cause of pain (e.g., the wound) has been cured or has healed. Unrelieved acute pain, however, might lead to chronic pain. Chronic pain (also known as persistent pain) usually lasts longer than three months, beyond the healing period of tissue damage. Chronic pain normally originates with the initial trauma/injury but persists despite the fact that the injury has healed and no new tissue injury occurs. Pain signals remain active in the nervous system for weeks, months, or years. Physical effects include tense muscles, limited mobility, sleep disturbances and changes in appetite. Emotional effects include depression, anger, anxiety and fear of re-injury. Such emotional effects can hinder a person's ability to return to normal work or leisure activities. Post-surgical pain can also be divided into “superficial” and “deep”, and deep pain into “deep somatic” and “visceral”. Superficial pain comes from the damaged skin or superficial tissues and is sharp, well-defined and clearly localized. Deep somatic pain comes from injured ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly-localized. Visceral pain originates in the injured viscera (organs) and is usually more aching or cramping than somatic pain. Visceral pain may be well-localized, but often it is extremely difficult to locate, and several visceral regions produce “referred” pain when injured, where the sensation is located in an area completely unrelated to the site of injury. Post-surgical pain can also be neuropathic (i.e., neuropathic pain) in nature as the nervous system becomes injured. Peripheral neuropathic pain occurs when the lesion affects the peripheral nervous system (e.g., peripheral nerves, nerve roots and/or ganglia) and thus peripheral neuropathy takes place. Nerve damage by surgery can also result in nerve inflammation (neuritis) and neuralgia (pain in the distribution of the nerves). Central neuropathic pain may occur when the lesion affects the central nervous system (e.g., brain, cerebellum, spinal cord). Pain can result from neuroma (also known as “pseudoneuroma”) formation (e.g., traumatic neuroma following nerve injury as a result of surgery) that typically occurs at the end of injured nerve fibres as a form of ineffective, unregulated nerve regeneration commonly near a scar, either superficially (skin, subcutaneous fat) or deep (e.g., after a cholecystectomy). Pain from deafferentation can also occur if injured or axotomized nerve fibres degenerate thus completely or partially interrupting afferent nerve impulses. Causalgia, a syndrome of sustained burning pain, allodynia, and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes can also happen. In fact, pain can arise from any tissue or part of the body where external trauma or injury such as a cut, puncture, incision, tear, or wound into tissue of an individual (including those that arise from all surgical procedures, whether invasive or non-invasive) occurs. Finally, pain can differ in quantity (e.g., mild, moderate, severe) and quality (e.g., aching, burning, tingling, electrical, stabbing), it can include abnormal sensations (e.g., dysesthesia, paresthesia) and it can be continuous, intermittent or oscillating in intensity.
Different animal models and studies on postoperative incisional pain are reported in the state of the art (T. J. Brennan et al. Pain 1996, 64, 493-501; P. K. Zahn et al. Regional Anesthesia and Pain Medicine 2002, Vol. 27, No 5 (September-October), 514-516).
Finally, it is important to emphasize that there is a need to provide a new form of prevention and/or treatment of post-surgical acute and chronic pain, allodynia, hyperalgesia and abnormal sensations secondary to nerve (peripheral neuropathy) and tissue (superficial and deep somatic and visceral) injury developing during and/or after surgery.